The Mr. Burns balance and the evolution of ageing.

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Post written by Juan A. Rodríguez & Arcadi Navarro

When
relatives and friends ask me about my PhD project, I tend to refer
them to an anecdote seen at The Simpson's TV series. In episode 12 of
the 11th
season, The
Mansion Family,
Mr.
Burns visits the Mayo Clinic
and a physician says to the tycoon:

- “Mr. Burns, I'm afraid
you are the sickest man in the United States. You have everything.”

However,
according to the doctor, all of his diseases were “in
perfect balance”.
This created a situation where diseases got “stuck”
trying to access all at a time through a metaphoric door to the body,
misleading Burns to believe that he is indestructible. In reality,
this was posing a delicate situation for Burns since “even
a slight breeze [could
kill him]”.

This
concept of co-occurrence of diseases in a same individual has a name:
comorbidity. Five to six years ago Dr. Arcadi Navarro was on a train
reading about this phenomenon. Interestingly, on top of direct
comorbidities, where several diseases occur at the same time, inverse
comorbidities are also possible, with certain conditions
reducing the probability of others.
For instance: individuals with Down's syndrome or Alzheimer's have
reduced incidence of cancer. This issue has strong links with ageing
and senescence. More than 60 years ago, George C. Williams, an
American evolutionary biologist devised a theory on why any organisms
would experience physical decay with age, that is, senescence: The
Antagonistic Pleiotropy Theory. William’s theory is based
on the concept of pleiotropy (the same gene affecting two or more
traits) and states that genetic variants explaining the frailty of
old people or increasing our risk for late-onset conditions may exist
in the human genome because they confer a benefit increasing our
reproductive fitness while we are on fertile stages. That is, if a
given genetic variant has antagonistic effects, positive for the
organism when young but deleterious when old, it may be favored by
natural selection.

Evaluating
this hypothesis in our species has been remarkably difficult, given
the historical scarcity of data on the genetic architecture of
disease, However the huge amount of data from genome-wide association
studies (GWAS) accumulated over the last decade allows for a first
approach to these questions.

We started
by collecting genetic markers associated with all diseases with GWAS
data available from public databases. Then, after a revision of
medical literature, we assigned an age of onset to each of the
diseases and started setting links between different diseases which shared genetic markers. These could be indicative of pleiotropy. If
Williams was right there should be an statistically significant
excess of antagonistically pleiotropic variants in our genomes; that
is, an excess of variants that, while offering protection for an
early onset condition would, on the other hand, increase risk for
later onset diseases.

The
difficulty here is that we cannot know a
priori when
a human stops being “young” and enters
“old age”. We had to be agnostic and let data speak for itself.
To do so, we considered every possible age threshold bewteen 10 and
60 years old. We did find a significant excess of antagonistic
pleiotropies when considering age thresholds between 40 and 50 years
old, peaking at around 46. This is quite remarkable, since this period overlaps with
female menopause and with known
anthropological
data on the survival time of our ancestors. Taken at face value, this
would mean that these ages constitute a biologically relevant
frontier for disease in human species.

Current life quality and
healthcare have improved life after menopause, particularly during
the last century. But it’s highly likely that if you were an
Australopithecussp.
you would be already dead by that age or even before, so taking the
maximum possible profit during fertile years in terms of reproductive
success should be a priority for natural selection, despite
detrimental effects later on. In the end, the body may eventually pay
for the effect of those protective variants. Just as an example,
variants surrounding the WNT4
gene
are associated with protection from ulcerative colitis, despite risk
for Dupuytren's
disease, a permanent contracture in the hand where fingers cannot be
fully extended. Thus, besides providing an evolutionary explanation
to the roots of ageing in our species, our approach can be used for
identifying comorbidities between diseases that so far have remained
unrelated. In a sense, we are showing that nature subscribes to the
motto "Live fast, die young"

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